Aurone derivative-containing composition for diagnosis

A composition and compound technology, applied in the directions of preparations for in vivo experiments, organic chemistry, in vivo radioactive preparations, etc., can solve the problems of low permeability, no input, low clearance rate, etc., and achieve the effect of high binding specificity

Inactive Publication Date: 2009-09-30
NAGASAKI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, several derivatives comprising Congo red or thioflavine T (thioflavine T) as the parent structure have been reported as probe compounds (Japanese Patent Application Publications No. 2004-250407 and 2004-250411; Klunk W.E. et al., Annals of Neurology Vol.55, No.3, March 2004, 306-319), but these compounds still have many problems, including: low specificity to amyloid β protein, low permeability through the blood-brain barrier, and due to the Nonspecific binding in the brain results in low clearance
Therefore, these reported compounds are not currently in practical use for the diagnosis of diseases associated with amyloid deposition

Method used

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  • Aurone derivative-containing composition for diagnosis
  • Aurone derivative-containing composition for diagnosis
  • Aurone derivative-containing composition for diagnosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] experimental method

[0092] (1) Reagents and instruments

[0093] As radioactive iodine-125 ( 125 I) using IODINE-125 (185 MBq) from Amersham Bioscience. For reverse-phase HPLC, a Cosmosil 5C18-AR column (4.6 x 150mm) from Nacalai Tesque was used, and ultrapure water (A) and acetonitrile (B) were used as eluents at a mixing ratio of A:B=30:70 , with a flow rate of 1.0 mL / min. Mass spectra were obtained on a JEOL IMS-DX instrument. Amyloid beta protein (Human, 1-42) [TFA form] was purchased from Peptide Institute. Other reagents are grade specific. Obtained on a Varian Gemini 300 spectrometer 1 H-NMR spectrum with tetramethylsilane as internal standard.

[0094] (2) Synthesis of 2-benzylbenzofuranone derivatives

[0095] Synthesis of methyl 2-(2-(methoxy-2-oxyethoxy)-5-bromobenzoate (compound 1)

[0096] To a solution of methyl 2-hydroxy-5-bromobenzoate (1.5 g, 6.49 mmol) in acetone (10 mL) was added K 2 CO 3 (2.7g). Ethyl bromoacetate (1.3 mL) was then adde...

Embodiment 2

[0154] experimental method

[0155] (1) Reagents and instruments

[0156] The same reagents and equipment as in Example 1 were used.

[0157] (2) Synthesis of 2-benzylbenzofuranone derivatives

[0158] Synthesis of methyl 2-((ethoxycarbonyl)methoxy)-5-iodobenzoate (compound 21)

[0159] To a solution of methyl 2-hydroxy-5-iodobenzoate (2.0 g, 7.19 mmol) in acetone (10 mL) was added K 2 CO 3(2.7g). Subsequently, ethyl bromoacetate (2.0 mL) was added dropwise thereto with stirring. The mixture was heated to reflux for 3 hours. After the reaction was complete, the solvent was evaporated. The residue was dissolved in pure water (100 mL), followed by extraction with ethyl acetate (100 mL). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated to give compound 21. Yield: 2.62g (Yield: 99%) 1 H NMR (300MHz, CDCl 3 ) 1.29(t, J=7.2Hz, 3H), 3.90(s, 3H), 4.25(q, J=6.0Hz, 2H), 4.69(s, 2H), 6.66(d, J=8.7Hz, 1H ), 7.71 (dd, J=2.4, 2.4Hz, 1H), 8.12 (...

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Abstract

A composition for the diagnosis of diseases relating to amyloid which contains either a compound represented by the general formula (I): [wherein X represents O, etc.; R, R, R, R, R, R, and R each represents hydrogen, etc.; R represents halogeno, etc.; and R represents dimethylamino, etc.] or a compound obtained by labeling that compound with a radionuclide or contains a pharmaceutically acceptable salt of any of these compounds. The compound represented by the general formula (I) has high bonding specificity for amyloid ss-protein, is apt to highly pass through the blood-brain barrier, and has the property of rapidly disappearing from the areas excluding senile plaques in the brain.

Description

technical field [0001] The present invention relates to diagnostic compositions comprising 2-benzylbenzofuranone derivatives. The composition of the present invention can be used in the diagnosis of amyloid-related diseases such as Alzheimer's disease. Background technique [0002] With the acceleration of population aging in recent years, the increase in the number of patients suffering from dementia-related diseases such as Alzheimer's disease (AD) has become one of serious social problems. Hasegawa Scale (Hasegawa Scale), ADAS and MMSE are currently existing methods for clinical diagnosis of AD. All of these methods quantitatively assess the decline in cognitive function in individuals suspected of having AD and are commonly used. In addition, imaging diagnostic methods (MRI, CT, etc.) are also supplemented. However, these diagnostic methods are insufficient to definitively diagnose AD, and developing senile plaques and neurofibrils need to be confirmed in biopsy of th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/00C07D307/83
Inventor 小野正博
Owner NAGASAKI UNIVERSITY
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